The present invention relates to the application of hyperpolarized gases to magnetic resonance imaging (MRI).
In particular, this invention relates to a method for the dynamic regional measurement of lung perfusion and ventilation using magnetic resonance imaging based on the use of hyperpolarized noble gases.
In the techniques of nuclear magnetic resonance (NMR) a magnetic field acts on the nuclei of atoms with fractional spin quantum numbers and polarizes them into alignment within some selected orientations. During measurements, radio-frequency pulses of given resonance energy are applied that flip the nuclear spins and disturb the orientation distribution; then the nuclei return (relax) to the initial state in a time dependent exponential fashion, thus giving signals which are electronically processed into recordable data. When the signals are spatially differentiated and of sufficient level, the data can be organized and displayed as images on a screen. For instance, computing the signals generated by the protons (1H) of the water in contact with organic tissues enables to construct images (MRI) allowing direct visualization of internal organs in living beings. This is therefore a powerful tool in diagnostics, medical treatment and surgery.
There exist proton MRI techniques for tissue perfusion measurements, such as contrast enhanced MRI using very short echo time sequences (Berthezxc3xa8ne Y et al., Contrast enhanced MR imaging of the lung: assessment of ventilation and perfusion. Radiology 7992, 183: 667-672; Habutu H. et al. Pulmonary perfusion: qualitative assessment with dynamic contrast-enhanced MRI using ultra-short TE and inversion recovery Turbo FLASH, Magn. Reson. Med. 1996; 36: 503-508) or spin labelling techniques (Mai V M and Berr S S: MR perfusion imaging of pulmonary parenchyma using pulsed arterial spin labelling techniques: FAIRER and FAIR. J. Magn. Reson. Imag. 1999; 9: 483-487) but are unfortunately difficult to perform in the lungs. Lung perfusion MRI is first hampered by a low proton density. Magnetic susceptibility effects due to the numerous air/tissue interfaces also shorten the effective transverse relaxation time T2 (Durney C. et al.xe2x80x94Cutillo, A G, editor; Application of Magnetic Resonance to the study of lung. Armonk: Futura Publishing Company; 1996, p. 141-175).
Recently, it has been proposed to use in the MRI of patients isotopes of some noble gases in hyperpolarized form. Although the signal from these isotopes in the naturally polarized state is very weak (5000 times weaker than from 1H), hyperpolarization will effectively raise it about 104 to 105 times. Furthermore, the spin relaxation parameters of the hyperpolarized gases are very strongly influenced by the nature of the environment in which they distribute after administration (i.e. they provide a detailed array of signals of different intensities), which makes them very interesting contrast agents in MR imaging.
Hyperpolarizing noble gases is usually achieved by spin-exchange interactions with optically excited alkali metals in the presence or in the absence of an externally applied magnetic field (see e.g. G. D. Cates et al., Phys. Rev. A 45 (1992), 4631; M. A. Bouchlat et al. Phys. Rev. Lett. 5 (1960), 373; X. Zeng et al., Phys. Rev. A 31 (1985), 260). With such techniques, polarization of 10% or more is possible, the normal relaxations (T1, T2) being so long (from several minutes to days in the case of Xe ice that subsequent manipulations (use for diagnostic purposes) are quite possible. Otherwise, hyperpolarization can be achieved by metastability exchange, for instance by exciting 3He to the 23S1 metastable state which is then optically pumped with 1083 nm circularly polarized laser light to the 23P0 state. Polarization is then transferred to the ground state by metastability exchange collisions with the ground state atoms (see e.g. L. D. Schaerer, Phys. Lett. 180 (1969), 83; F. Laloe et al., AIP Conf. Proc. #131 (Workshop on Polarized 3He Beams and Targets, 1984).
WO-A-95/27438 discloses use of hyperpolarized gases in diagnostic MRI. For instance, after having been externally hyperpolarized, the gases can be administered to living subjects in gaseous or liquid form, either alone or in combination with inert or active components. Administration can be effected by inhalation or intravenous injection of blood that has previously been extracorporally contacted with the gas. Upon administration, the distribution of the gas within the space of interest in the subject is determined by NMR, and a computed visual representation of said distribution is displayed by usual means. No practical example of administration of a parenteral contrast agent composition or formulation, no identification of the additional components is provided.
In an article by H. Middleton et al., Mag. Res. Med. 33 (1995), 271, there is disclosed introducing polarized 3He into the lungs of dead guinea-pigs and thereafter producing an NMR image of said lungs.
P. Bachert et al. Mag. Res. Med. 36 (1996), 192 disclose making MR images of the lungs of human patients after the latter inhaled hyperpolarized 3He.
WO-A-99/47940 discloses a method for imaging pulmonary and cardiac vasculature and evaluating blood flow using dissolved polarized 129Xe. This method is carried out by positioning a patient in a magnetic resonance apparatus and delivering polarized 129Xe gas to the patient via inhalation such as with a breath-hold delivery procedure, exciting the dissolved gas phase with a large flip angle pulse, and generating a corresponding image.
Compared to the clinical scintigraphy technique used for functional pulmonary ventilation and perfusion assessment, and based on the inhalation of radioactive gas (133Xe, 81Kr), noble gas MRI offers an improved spatial and temporal resolution without ionizing radiation (Alderson P O and Martin E C, Pulmonary embolism: diagnosis with multiple imaging modalities, Radiology 1987; 164:297-312). However, MRI using laser-polarized gas has failed, to date, to assess lung perfusion function in a satisfactory way. For instance, the method according to WO-A-99/47940 is not sufficiently accurate, due to the difficulties to distinguish the signals from the gas dissolved in tissues and the gas dissolved in the blood. Furthermore, one has to deal with low signal intensities from dissolved gas.
Therefore, the problem underlying the present invention was that of providing a method for simultaneously assessing lung perfusion and ventilation, which could overcome the drawbacks of the prior art methods, both those based on proton MRI techniques and those based on hyperpolarized noble gases.
Such a problem has been solved, according to the invention, by a method for the assessment of pulmonary ventilation and lung perfusion through Magnetic Resonance Imaging (MRI), comprising the steps of:
positioning a human subject in an MRI apparatus,
delivering a hyperpolarized noble gas to the subject by inhalation, followed by a breath-hold period, during which a bolus of a contrast agent for MRI is injected intravenously,
acquiring, during said breath-hold period, at least one MR image of the lungs prior to said bolus intravenous injection and at least one MR image thereafter.
The MRI image acquired after the bolus intravenous injection is taken during the passage of the contrast agent in the pulmonary vasculature.
The contrast agent for MRI used in the present method preferably contains a compound selected among the group comprising superparamagnetic iron oxide nanoparticles (SPIO), ultrasmall superparamagnetic iron oxide nanoparticles (USPIO), gadolinium complexes and manganese complexes.
The SPIO and USPIO are preferably employed as stabilized suspensions.
Examples of suitable suspensions of SPIO and USPIO are provided by the following products:
SBPA (Bracco Research Genevaxe2x80x94Pochon S. et al., Circulating superparamagnetic particles with high T2 relaxivity, Acta Radiologica 1997; 38 (suppl. 412): 69-72): Fe3O4 particles coated with dipalmitoylglycerophosphatidic acid and a block ethyleneoxidepropyleneoxide copolymer (Synperonic F108 from ICI),
ENDOREM(copyright) (AMI 25) and SINEREM(copyright) (AMI 227) (Guerbet): Fe3O4 particles coated with dextran; AMI 21: Fe3O4 particles coated with siloxane; (Jung C W et al. Physical and chemical properties of superparamagnetic iron oxide MR contrast agents: Ferumoxides, ferumoxtran, ferumoxsil; Magnetic Resonance Imaging 13: 661-674 (1995)),
RESOVIST(copyright) or SHU 555A (from Scheringxe2x80x94Hamm B et al., A new superparamagnetic iron oxide contrast agent for magnetic resonance imaging; Investigative Radiology 29; S87-S89 (1994)): Fe3O4 particles coated with carboxydextran,
NC100150 (from Nycomedxe2x80x94Kellar Ke et al. NC100150, a preparation of iron oxide nanoparticles ideal for positive-contrast MR angiography, Magnetic Resonance Materials in Physics, Biology and Medecine 8: 207-213 (1999)): Fe3O4 particles coated with starch.
The injected dose of the contrast agent containing SPIO or USPIO is preferably in the range of about 0.05 to about 5 mg iron/kg of body weight. Most preferably, such a dose is comprised in the range of about 0.1 to about 1 mg iron/kg.
Examples of suitable Gadolinium complexes are the following:
Gd-DTPA (Magnevist(copyright) from Schering), Gd-DOTA (Dotarem(copyright) from Guerbet), Gd-HPDO3A (ProHance(copyright) from Bracco), Gd-BOPTA (MultiHance(copyright) from Bracco), Gd-DTPA-BMA (Omniscan(copyright) from Nycomed), GADOVERSETAMIDE (complex of gadolinium with DTPA-bis(methoxyethylamide) from Mallinckrodt), Gadomer-17 (dendrimer from Scheringxe2x80x94Qian Dong et al., Magnetic Resonance Angiography with Gadomer-17; Investigative Radiology: 33, 9, 699-708 (1998)), Gd-EOB-DTPA (Gd-ethoxybenzyl-DTPAxe2x80x94Eovist(copyright) from Schering); Gadobutrol (Gadovist(copyright) from Schering), MS 325 (Complex of gadolinium with (2-(R)-(4, 4-diphenylcyclohexyl)phosphonooxymethyldietilentriaminpenaacetic acid trisodium saltxe2x80x94ANGIOMARK(copyright) from Mallinckrodtxe2x80x94Lauffer R B et al.; MS 325: a small-molecule vascular imaging agent for magnetic resonance imaging; Academic Radiology 3: S356-S358 (1996)).
These complexes are administered intravenously in a dose of 0.05 to 0.5 mmol Gd/kg.
As an example of Manganese complexes, it is cited TESLASCAN(copyright) or MANGAFODIPIR, a Manganese complex Mn-DPDP from Nycomed (Lim K O et al., Hepatobiliary MR imaging first human experience with Mn-DPDP; Radiology 178: 79-82 (1991)
The hyperpolarized noble gas is selected from the group comprising 3He, 129Xe, 131Xe, 83Kr and 21Ne, and mixtures thereof. 3He is particularly preferred.
It is also possible to use mixtures of the hyperpolarized noble gas with nitrogen, air and other physiologically acceptable gases.
The hyperpolarized noble gas is delivered to the human subject in an amount of about 0.1 liter to about 2 liters, then the subject should hold the breath, preferably for at least 10 seconds.
The preferred amount for 3He is about 0.1 to about 1 liter
The method according to the present invention proposes for the first time the combined use of a contrast agent, so far used only in proton MRI techniques, and a hyperpolarized noble gas. Through this combination surprisingly good results have been obtained in the assessment of the pulmonary ventilation and, above all, of the lung perfusion. This is of outermost importance for the diagnosis of defects and alterations at the pulmonary blood vessels.
The principle on which the present method is based is at the same time quite simple and very inventive. It will become clear from the subsequent detailed description of the invention, but it is worthwhile giving at least a very rough idea thereof.
Once a subject has inhaled the hyperpolarized noble gas, the NMR apparatus detects a certain signal, whose intensity, as known, progressively decreases. If a bolus of one of the above-mentioned contrast agents is injected right after inhalation of the hyperpolarized gas, the first pass of the contrast agent in the pulmonary vasculature brings about a marked increase of the magnetic susceptibility difference between the alveoli spaces and tissue.
In NMR, static field inhomogeneities generated by these magnetic susceptibility differences induce increased dephasing effects of the transverse nuclear magnetization which in turn results in a reduced NMR signal intensity.
It has been hereby demonstrated that this effect leads to a strong signal depletion during the bolus pass that can in turn be used to estimate the regional pulmonary blood volume.
The above-mentioned signal depletion does not occur if the pulmonary vessels are not totally perfused, because in the presence of any obstruction in a vessel, there is no bolus pass.
Therefore, from the local variations of the profile of the signal intensity it is possible to conclude whether any alterations are present or not.
The characteristics and the advantages of the present invention will become more apparent from the following description of certain preferred but not limiting embodiments thereof, made with reference to the appended drawings.